1. Field of the Invention
The substituted alkylidenedithio-bis-(substituted)phenols used in the invention are compounds of the type disclosed in U.S. Pat. Nos. 3,576,883, 3,786,100, 3,862,332 and 3,897,500 and can be made by the methods disclosed in those patents. One of the alkylidenedithio-bis(substituted)phenols, 4,4'-(isopropylidenedithio)bis(2,6-di-tert-butyl) phenol), is known by the generic name "probucol", and is used as a hypocholesterolemic drug. Probucol is known to lower serum cholesterol, and to reduce both high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol. It has been shown to inhibit oxidative modification of LDL, an effect which has been hypothesized as possibly inhibiting atherogenesis. Naruszewicz et al., Journal of Lipid Research, Vol. 25, 1206 (1984); and Parthasarathy et al., J.Clin.Invest., Vol. 77, 641 (1985).
Interleukin-1 (IL-1) is the name for a family of molecules which have multiple biological effects. The name interleukin-1 was proposed in 1979: and earlier literature reports refer to it by some other name. Murphy, British Journal of Rheumatology, 1985; 24(suppl 1): 6-9, and Oppenheim et al., Immunology Today, Vol. 2, 45-55 (1986). IL-1 is secreted by stimulated macrophages, and has several significant biological effects, such as mediation of T-lymphocyte proliferation and pyrogenic and proinflammatory effects.
IL-1 activities are summarized in the two above papers. IL-1 has been described to mediate the acute phase response in inflammation, and to have pyrogenic and proinflammatory effects IL-1 induces connective tissue changes, and has been demonstrated to induce the release of degradative enzymes from mesenchymal cells that are present at the sites of bony erosion in inflammatory disease states, such as rheumatoid arthritis. Billingham, Brit.J.Rheumatology, 1985:24(suppl 1):25-28. Dayer. Brit.J. Rheumatology, 1985:24(suppl 1):15-20. The production of acute phase proteins in the hepatocytes during the acute phase of inflammation is mediated by IL-1 and other cytokines, such as IL-6. Whicher, Brit.J.Rheumatology, 1985:24(suppl 1):21-24.
IL-1 is also involved as a mediator in the inflammatory skin disease, psoriasis. Camp et al., J. Immunology 1986: 137: 3469-3474, and Ristow, Proc. Natl. Acad. Sci. U.S.A. 1987: 84: 1940-1944. It is cytotoxic for insulin producing beta cells in the pancreas, and is thus a causative factor in the development of some forms of diabetes mellitus. Bendtzen et al., Science 1986: 232: 1545-1547 and Marx, Science 1988: 239: 257-258, IL-1 also appears to be involved in the development of atherosclerotic lesions or atherosclerotic plaque. Marx, Science 1988: 239: 257-258. IL-1 stimulates growth and proliferation of vascular smooth muscle cells, an effect which is greater in the absence or suppression of endogenous prostaglandins, which could lead to thickening of vascular walls, such as occurs in atherogenesis. Libby et al., Fed. Proc. Mar. 1, 1987: Vol. 46, no. 3: 975, Abstract 3837.
It would be advantageous to control the release of IL-1, and to be able to treat IL-1-mediated effects It would also be advantageous to control or treat IL-1 mediated inflammation, without production of concomitant side effects known to accompany the use of antiinflammatory steroids and non-steroidal antiinflammatory agents.